Electrochemically promoted three-component synthesis for the functionalization of N-sulfonylformamidine

Electrochemically promoted three-component synthesis for the functionalization of N-sulfonylformamidine | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 3 June 2025 V1 Latest version Share on Electrochemically promoted three-component synthesis for the functionalization of N-sulfonylformamidine Authors : Xue-Yang Guo , Shi-Jie Bo , Li-Ming Zhang , Li-Rong Wen , Weisi Guo 0000-0001-6688-4679 , and Lin-Bao Zhang 0000-0002-8334-4188 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174894142.26584790/v1 162 views 120 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract A one-pot synthetic strategy was developed using electrochemical methods to convert sulfonamides into N -sulfonylformamidines, followed by the direct functionalization of the C-H bond through electrochemical oxidation. Subsequently, modification was achieved for the first time by introducing azide groups via imide ions under Lewis acid catalysis, utilizing TMSN 3 as the nucleophilic reagent. This strategy is compatible with a wide range of functional groups, and its utility has been demonstrated through scale-up experiments and derivatization reactions. Cite this paper: Chin. J. Chem. 2025 , 43 , XXX—XXX. DOI: 10.1002/cjoc.202500XXX Electrochemically promoted three-component synthesis for the functionalization of N -sulfonylformamidine Xue-Yang Guo, Shi-Jie Bo, Li-Ming Zhang,* Li-Rong Wen,* Weisi Guo, and Lin-Bao Zhang * State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and Molecular Engineering, Qingdao University of Science & Technology, Qingdao 266042, China not-yet-known not-yet-known not-yet-known unknown Keywords Electrocatalysis | N-sulfonylformamidine | Three-component synthesis | Functionalization Comprehensive Summary A one-pot synthetic strategy was developed using electrochemical methods to convert sulfonamides into N-sulfonylformamidines, followed by the direct functionalization of the C-H bond through electrochemical oxidation. Subsequently, modification was achieved for the first time by introducing azide groups via imide ions under Lewis acid catalysis, utilizing TMSN3 as the nucleophilic reagent. This strategy is compatible with a wide range of functional groups, and its utility has been demonstrated through scale-up experiments and derivatization reactions. Background and Originality Content As a novel type of multifunctional molecular unit, N -sulfonylformamidine is commonly found in natural products and pharmaceutical compounds, playing a significant role in medicinal chemistry and synthetic methodologies (Figure 1). [1] In the realm of drug development, famotidine and ethambutidine are recognized as anti-ulcer medications, [2a] while compound III has potential as an anti-osteoporotic agent. [2b] Furthermore, N -sulfonylformamidines act as bioactive pharmacophores, exhibiting antiproliferative and anticancer properties. [2c,2d] The advancement of these derivatives has enriched the molecular library within medicinal chemistry and has facilitated the creation of innovative therapeutic agents. Figure 1 Bioactive molecules containing the structure of N -sulfonylformamidine. N -sulfonylformamidines have garnered significant attention in the field of synthetic chemistry over the past few decades due to their unique properties. Synthetic studies have primarily been conducted through two- or three-component reactions (Scheme 1). In two-component synthetic methods, sulfonamides or sulfonyl azides can be directly condensed with amides or amines; however, these reactions typically require the assistance of oxidizing agents, metal catalysts, photocatalysis, or electrocatalysis to ensure a smooth progression of the reaction (Scheme 1a). [3] Additionally, three-component coupling reactions involving sulfonamides and sulfonyl azides with terminal alkynes, as well as ammonium chlorides or amines, have been successfully executed in copper metal-catalyzed systems, resulting in the efficient synthesis of amidines (Scheme 1b). [4] In addition to these two common approaches, other innovative three-component synthesis strategies are emerging. [5] In 2020, Phukan’s team successfully synthesized sulfonylformamidines through a one-pot reaction involving tertiary alkyl isonitrile and N , N -dibromoaryl sulfonamide, with the addition of nitrile and water. [5a] However, most current studies have concentrated on the synthesis of N -sulfonylformamidines, and there is a relative lack of research on structural modifications, which significantly limits the further application of these compounds. Therefore, there is an urgent need to develop a rapid and convenient method for modifying N -sulfonamidines. In recent years, electrochemical organic synthesis has made significant advancements in the field of alkoxylation reactions, allowing for the functionalization of organic molecules without the need for chemical reagents or protecting groups. [6] A notable reaction in this area is electrochemical oxidation, which employs electrocatalysis to facilitate the α -position functionalization of amines in alcohol solvents, leading to the formation of N , O -acetals. [7a] In addition, the applicability of the electrochemical oxidation method continues to broaden, extending from carbamates to a diverse array of substrates. [7b,7c] It has been successfully employed in the synthesis of α -alkylated and α -alkynylated saturated N -heterocyclic compounds, as well as in organozinc-mediated selective methylation reactions, among others. [8] Electrochemical oxidation is a method that employs organic electrochemical technology, which relies on the loss and transfer of electrons at the electrode/solution interface to facilitate chemical reactions and achieve the conversion of electrical and chemical energy. [9] Electric current serves as an economical, sustainable, and intrinsically safe medium that can replace conventional chemical oxidizing or reducing agents. [10] Based on our strong interest in organic electrochemical synthesis, [11] we developed an electrochemically promoted one-pot synthesis strategy for the functionalization of N -sulfonylformamidine through C sp3 -H activation. By integrating the oxidation of sulfonamide with DMF-DMA and the electrochemical oxidation reaction, we successfully synthesized N -sulfonylformamidine and achieved functionalization at its α -position, thus providing a alternative way for the access to its derivatives (Scheme 1c). This method requires no metal catalyst or additional oxidants and can be efficiently performed in air at ambient temperature, providing an environmentally friendly, mild, and cost-effective solution for the structural modification of N -sulfonylformamidines. This discovery not only broadens the application scope of organic electrochemical synthesis but also opens new avenues for the subsequent functionalization of N -sulfonylformamidines. Scheme 1 Developmental studies on N -sulfonylformamidine compounds Results and Discussion Initially, we selected p -toluenesulfonamide as a model substrate for our experiments. Following preliminary parameter optimization, we found that using methanol as a solvent at a constant current of 5 mA for 5.5 hours at ambient temperature produced alkoxides of sulfonylformamidines with a more stable E -configuration, achieving an E / Z ratio of 85:15 and yields as high as 88% (Table 1, entry 1). It is noteworthy that electricity plays a crucial role in this chemical transformation, as the reaction cannot proceed efficiently without it (Table 1, entry 2). Decreasing or increasing the constant current gave inferior yields compared to the standard conditions (Table 1, entries 3 and 4). Additionally, we investigated the effects of various electrode materials and found that using platinum or nickel electrodes as cathodes was ineffective in increasing yield (Table 1, entries 5 and 6). Furthermore, attempts to replace n -Bu 4 NPF 6 with other Table 1 Optimisation of the reaction conditions a not-yet-known not-yet-known not-yet-known unknown Entry Deviation from standard conditions Yieldb (%) 1 None 88 2 Without electricity n.r.c 3 3 mA 75 4 7 mA 79 5 GF(+)/Ni(-) instead of GF(+)/GF(-) 56 6 GF(+)/Pt(-) instead of GF(+)/GF(-) 72 7 Me4NHSO4 instead of n-Bu4NPF6 trace 8 n-Bu4NBF4 instead of n-Bu4NPF6 72 9 n-Bu4NOAc instead of n-Bu4NPF6 trace 10 Me4NCl instead of n-Bu4NPF6 n.r.c aReaction conditions: TsNH2 (0.1 mmol), n-Bu4NPF6 (0.15 mmol), DMF-DMA (0.3 mmol), MeOH (5 mL), graphite felt anode (10 mm x 10 mm x 5 mm), graphite felt cathode (10 mm x 10 mm x 5 mm), undivided cell, 5 mA, Air, r.t., 5.5 h, 5.13 F/mol, bIsolated yields, the E/Z ratios were determined by 1H NMR analysis of the crude product mixture. cn.r. = No reaction. electrolytes, such as Me 4 NHSO 4 , n-Bu 4 NBF 4 , n-Bu 4 NOAc, and Me 4 NCl, did not result in any improvement in yields (Table 1, entries 7-10). Having optimized the reaction conditions on hand, Scheme 2 Substrate scope a,b a Reaction conditions: 1 (0.1 mmol), n -Bu 4 NPF 6 (0.15 mmol), DMF-DMA (0.2 mmol), alcohol (5 mL), graphite felt anode (10 mm x 10 mm x 5 mm), graphite felt cathode (10 mm x 10 mm x 5 mm), undivided cell, 5 mA, Air, r.t., 5.5 h, 5.13 F/mol. b Isolated yields, the E / Z ratios were determined by 1 H NMR analysis of the crude product mixture. c n -Bu 4 NClO 4 as an electrolyte. we further investigated the adaptability of a variety of sulfonamides in the electrochemical oxidation reaction, compiling the results in Scheme 2. Initially, we explored various para -substituted sulfonamides. The results revealed that both electron-donating and electron-withdrawing groups, such as -Me ( 1a ), -Et ( 1c ), t -Bu ( 1d ), -OMe ( 1e ), and halogen groups ( 1f - 1i ), exhibited good tolerance in the reaction, yielding products 3a - 3i with yields ranging from 30% to 92%. Moreover, the structure of E - 3a was further confirmed by X- ray crystallography analysis (see the ESI for details; CCDC: 2441465 ). Even strong electron-withdrawing groups, such as -CF 3 ( 1j ), -OCF 3 ( 1k ), -CN ( 1l ), and -NO 2 ( 1m ), were compatible with the reaction, resulting in the expected products 3j , 3k , 3l , and 3m with yields of 68%, 87%, 72%, and 50%, respectively. Additionally, halogen groups (-F, -Cl, -Br), -CO 2 Me, and nitro groups (-NO 2 ) in the neighboring or interstitial positions of the benzene ring demonstrated good tolerance, with product yields ranging from 50% to 91% ( 3n - 3u ). Notably, even disubstituted or trisubstituted sulfonamides, such as 2,4-dichloro ( 1v ), 3,5-ditrifluoromethyl ( 1w ), and 2,4,6-trimethyl ( 1x ), achieved moderate to high yields. Interestingly, heterocyclic substrate, such as pyridine ( 1y ), was also successfully converted into the desired product ( 3y ). Moreover, when the right side of N -sulfonylformamidine is attached to a larger group, such as diethyl ( 1z , 1aa ), the reaction proceeds smoothly, and the Z -configuration product is more stable, exhibiting a Z / E ratio of 86:14. Subsequently, we evaluated the versatility of this electrochemical reaction by utilizing a range of alcohols. Common alcohols such as ethanol, n -propanol, and isopropanol exhibited good compatibility and were effectively transformed, resulting in moderate yields of the products ( 3ab - 3ad ). To demonstrate the utility and feasibility of the reaction, we conducted scale-up experiments (Scheme 3). Under standard conditions, we successfully synthesized the gram-scale compound 3a (83% yield, 1.27 g, 6.0 mmol), thereby providing an environmentally friendly and reliable method for the formation of functionalized modifications of N -sulfonylformamidine. Furthermore, the reaction can be performed on a 30 mmol scale. Scheme 3 Scale-up synthesis experiments N , O -acetals generated through electrochemical oxidation reactions have garnered significant attention due to their diverse applications as versatile intermediates in organic synthesis. [12] We first developed an efficient synthetic method to successfully introduce an azide group (-N 3 ) into N , O -acetal products modified by electrochemical oxidation (Scheme 4). Our investigation focused on various N , O -acetal products. The results demonstrated that both electron-donating and electron-withdrawing groups, such as -Me ( 3a ), -Et ( 3c ), t -Bu ( 3d ), and -CN ( 3l ), exhibited good tolerance in the reaction, with azides synthesized at high efficiencies, yielding between 62% and 95%. Furthermore, halogen groups (-Cl), nitro groups (-NO 2 ), and methyl groups (-Me) located in the interstitial or neighboring positions of the benzene ring were successfully reacted, yielding products at rates of 78%, 69%, and 75%, respectively. The establishment of this synthetic strategy not only expands the application scope of N , O -acetals but also provides robust support for subsequent studies. In addition, to evaluate the practicality of the derivatization reaction, we conducted a gram-scale synthesis experiment (Scheme 5). Under the established reaction conditions, we successfully synthesized gram-scale azide 4a with a yield of 70% (0.94 g), providing a solid foundation for further research. The azide group (-N 3 ) incorporated into product 4a can be further functionalized through a click reaction with phenylacetylene, efficiently yielding the 1,2,3-triazole ring compound 5a with a high yield of up to 80%. Moreover, the introduction of the BODIPY group using the same method facilitates the synthesis of BODIPY-conjugated triazole derivatives 5b , achieving a yield of 66%. Scheme 4 Later attempts to introduce azide a,b a Reaction conditions: 3 (0.1 mmol), TMSN 3 (3.0 equiv.), BF 3 ·Et 2 O (6.0 equiv.), MeCN (1.5 mL), Air, 0 o C → r.t., 3 h. b Isolated yields, the E / Z ratios were determined by 1 H NMR analysis of the crude product mixture. Scheme 5 Diversified pathways for ether 3a Additionally, the maximum fluorescence emission wavelength of compound 5b is approximately 519 nm (see Figure S6). Cell staining enables the evaluation of the compatibility of fluorescent molecules with cellular markers for applications within cells. We conducted fluorescence imaging studies on 4T1 cells using compound 5b , a BODIPY-conjugated molecule, with an excitation wavelength of 501 nm and an emission collection range of 490-550 nm. The results demonstrate that green fluorescence is uniformly distributed throughout the cytoplasm within the specified wavelength range. Compounds like 5b , which feature a BODIPY structure, can serve as fluorescent dyes and are suitable for a variety of biological applications, including bioimaging, fluorescence labeling, sensor development, and photosensitization. In order to gain insight into the reaction mechanism, square wave voltammetry (SWV) test was conducted (Figure 2), which indicated that the oxidation peaks of compound Int1 appeared at 1.67 V and 2.28 V, suggesting that the oxidation of Int1 occurred at the anode. Subsequently, free radical trapping experiments were conducted by adding free radical scavengers such as butylated hydroxytoluene (BHT), 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), and 1,1-diphenylethene (DPE), all of which were found to completely inhibit the reaction (Scheme 6). This result is indicative of the involvement of radical intermediates. Figure 2 Results of the square-wave voltammetry study. Square wave voltammogram obtained at a pulse height of 25 mV, a step height of 4 mV and a frequency of 10 Hz. Glassy carbon was used as the working electrode, a Pt wire as the counter electrode, and Ag/AgCl as the reference electrode. Scheme 6 Control experiments Based on the experimant results presented, we have outlined a potential mechanism for the electrochemical electrochemical oxidation reaction (Scheme 7). In the anodic oxidation step, compound Int1 is converted into the corresponding radical cation intermediate Int2 through a single electron transfer (SET) process. This is followed by deprotonation at the α -position and subsequent oxidation, resulting in the formation of the iminium ion intermediate Int3 , which can be detected using HPLC-MS. Immediately thereafter, intermediate Int3 is effectively trapped by reacting with the alcohol solvent, resulting in the formation of the target product 3a and facilitating the alkoxylation of N -sulfonylformamidines. Concurrently, protons are reduced at the cathode to generate H 2 , thereby eliminating the need for external oxidants or hydrogen acceptors. Scheme 7 Proposed reaction mechanism Conclusions In conclusion, we have developed a one-pot synthetic strategy utilizing electrochemistry for the conversion of sulfonamides to N -sulfonylformamides, followed by the direct functionalization of the C sp3 -H bond through the electrochemical oxidation reaction. This approach is environmentally friendly and highly efficient, eliminating the need for metal catalysts, chemical oxidants, or activating additives. It is capable of synthesizing a diverse array of N , O -acetal derivatives with various functional groups. Furthermore, this method offers a cost-effective and sustainable alternative for the synthesis of multifunctional N -sulfonylformamidines. A variety of azides can be easily prepared by subsequent treatment of the N , O -acetal derivatives with TMSN 3 , thereby expanding the synthetic applications. The practicality and scalability of this method have been validated through scale-up experiments and subsequent follow-up procedures, demonstrating promising application prospects. Experimental To an undivided cell (10 mL) equipped with a stir bar was add-ed substrate 1 (0.2 mmol, 1.0 equiv.), n -Bu 4 NPF 6 (0.15 mmol) and N , N -dimethylformamide dimethyl acetal (DMF-DMA, 0.2 mmol, 2.0 equiv.), followed by alcohol (5 mL). The flask was equipped with a rubber stopper, a graphite felt (GF) anode (10 mm x 10 mm x 5 mm) and a graphite felt (GF) cathode (10 mm x 10 mm x 5 mm). The reaction mixture was stirred and electrolyzed at a controlled current of 5 mA at room temperature for 5.5 h. After the reaction was completed (monitored by TLC), the reaction system was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether and ethyl acetate to give the product 3 . Supporting Information The supporting information for this article is available on the WWW under https://doi.org/10.1002/cjoc.2025xxxxx. Acknowledgement We thank the National Natural Science Foundation of China (21801152) and the Natural Science Foundation of Shandong Province (ZR2024MB055) for financial support. We thank the Youth Innovation Science and Technology Plan of Colleges and Universities in Shandong Province (2021KJ076). References 1. (a) Heitsch, H.; Becker, R. H. A.; Kleemann, H.-W.; Wagner, A. 3N-Methylbiphenylsulfonylurea and -carbamate substituted imidazo[4,5-b]pyridines. Potent antagonists of the ANG II AT1 receptors. Bioorg. Med. Chem. 1997 , 5, 673-678. (b) Bekhit, A. A.; Ashour, H. M. A.; Abdel Ghany, Y. S.; Bekhit, A. E.-D. A.; Baraka, A. 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DOI: 10.1002/cjoc.202500XXX A one-pot synthetic strategy was developed using electrochemical methods to convert sulfonamides into N -sulfonylformamidines, followed by the direct functionalization of the C-H bond through electrochemical oxidation. Subsequently, modification was achieved by introducing azide groups via imide ions under Lewis acid catalysis, utilizing TMSN 3 as the nucleophilic reagent. This strategy is compatible with a wide range of functional groups, and its utility has been demonstrated through scale-up experiments and derivatization reactions. Information & Authors Information Version history V1 Version 1 03 June 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords electrocatalysis n-sulfonylformamidine three-component synthesis Authors Affiliations Xue-Yang Guo Qingdao University of Science and Technology School of Chemistry and Molecular Engineering View all articles by this author Shi-Jie Bo Qingdao University of Science and Technology School of Chemistry and Molecular Engineering View all articles by this author Li-Ming Zhang Qingdao University of Science and Technology School of Chemistry and Molecular Engineering View all articles by this author Li-Rong Wen Qingdao University of Science and Technology School of Chemistry and Molecular Engineering View all articles by this author Weisi Guo 0000-0001-6688-4679 Qingdao University of Science and Technology School of Chemistry and Molecular Engineering View all articles by this author Lin-Bao Zhang 0000-0002-8334-4188 [email protected] Qingdao University of Science and Technology School of Chemistry and Molecular Engineering View all articles by this author Metrics & Citations Metrics Article Usage 162 views 120 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Xue-Yang Guo, Shi-Jie Bo, Li-Ming Zhang, et al. Electrochemically promoted three-component synthesis for the functionalization of N-sulfonylformamidine. Authorea . 03 June 2025. DOI: https://doi.org/10.22541/au.174894142.26584790/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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